Background

Excessive bleeding is a common complication in cardiac
surgery, and may result in the need for red blood cell (RBC) transfusion.
Intraoperative bleeding during cardiac surgery is often treated with
coagulation factor concentrates (CFCs). As yet, however, their efficacy has not
been conclusively determined.

Since 1980 our knowledge of damage from transfusion has
increased. Risks include infection, effects on the immune system, transfusion-related
acute lung injury and risks due to the age of transfused blood (Isbister et al.
2011). Healthcare systems need to also be aware of the associated costs. As
doctors it is our challenge and duty to reduce preventable damage from blood
transfusion.

Patient blood management

The evidence-based multidisciplinary approach to optimising
care of patients who may need transfusion is known as patient blood management (PBM).
We know there is considerable variation in perioperative blood transfusion rate.
For example, an analysis of 102,470 patients who underwent coronary artery
bypass graft surgery at 792 hospitals in the United States found that rates of
blood transfusion ranged from 7.8% to 92.8% for red blood cells
(Bennett-Guerrero et al. 2010). PBM can also reduce the need for blood
transfusions. In cardiac surgery, a study of Jehovah’s Witnesses, who refuse
blood products, found no difference in morbidity and mortality if patients are evaluated
with a multidisciplinary approach to blood management (Moraca et al. 2011).

At Isala Clinics, we have researched patient blood
management, including tailor-made transfusion protocols (Bilecen et al. 2014), and
the role of point-of-care testing and fibrinogen concentrate (Bilecen et al.
2013). We implemented a specific transfusion protocol for cardiac surgery, and
conducted an intervention study to evaluate its effects on transfusion and
clinical events (Bilecen et al. 2014). The protocol included giving component
therapy and fibrinogen at the end of the schedule. If we measured fibrinogen
less than 1g/L we added 2g of extra fibrinogen. If it was more than 1g/L based
on the Clauss measurement, we did not give fibrinogen. The cardiac surgery-specific
transfusion protocol resulted in fewer patients transfused with RBCs and fresh frozen
plasma (FFP) and a lower incidence of myocardial infarction.

Fibrinogen concentrate therapy

We conducted a cohort study to evaluate the effect of
fibrinogen concentrate therapy on postoperative blood loss and transfusion and occurrence
of clinical events in complex cardiac surgery; 264/1075 patients received
fibrinogen concentrate during surgery (Bilecen et al. 2013). There was no
reduction in postoperative blood loss and transfusion (intensive care unit
[ICU] blood loss: OR 1.02 (0.91-1.14) and ICU transfusion: OR 1.14 (0.83-1.56) and
no increase in risk for adverse clinical events. However, the haemostatic
effect may have been attenuated by the low doses and relatively late
administration of fibrinogen concentrate therapy.

The primary outcome of the study was intraoperative blood
loss measured between intervention and closure of the chest when surgery ended.
Secondary outcomes included the measured blood loss at 1, 3, 6,12 and 24 hours
after the intervention; the proportion of patients who received transfusion;
and number of units of RBCs, FFP or platelet concentrate.

The aim was to achieve surgical haemostasis after heparin
reversal. It was the surgeons’ decision when to start the 5-minute bleeding time.
Once patients had bled for 5 minutes they were entered into the treatment
algorithm if they were bleeding >60 mL and <250 mL. The intervention was
considered to have started on initiation of infusion of the study medication (Figure
1).

Over the four years of the trial, over 700 patients had
complex cardiac surgery, of which 40% were eligible for the trial. Of the
eligible patients, 43% did not agree to participate; 203 patients agreed to
participate, of which 73 (36%) experienced no intraoperative bleeding and 10
were excluded for other reasons. We suggest that the high number of patients
that experienced no intraoperative bleeding may be due to the Hawthorne
effect—performing differently when being observed. This group of patients had
very extensive surgical haemostasis before we started with the 5 minutes bleeding
time, much longer than usual. The surgeons may have perceived that they were a better
surgeon if they were not included in the trial, and also that after closure of
the chest the microvascular bleeding was now the problem for the
anaesthesiologist.

The patients were randomised to receive either the placebo
or the intervention drug in doses between 60ml and 250ml. The fibrinogen doses
were calculated based on plasma fibrinogen levels at the end of cardiopulmonary
bypass measured using the Clauss method (Figure
2).

Results

Primary outcome

Among patients with intraoperative bleeding who received
infusion of fibrinogen concentrate, compared with placebo, there was no significant
difference in blood loss measured from the time of the fibrinogen infusion and chest
closure (p = 0.19) (Table 1).

fibrinogen group

(median, 50 mL; IQR, 29-100 mL)

control group

(median, 70 mL; IQR, 33-145 mL)

absolute difference:

20 mL (95% CI, −13 to 35 mL)

Cumulative 24-hour blood loss was lower in the fibrinogen
group compared with placebo (p = 0.047).

The duration of primary outcome collection was 4.2 minutes
(95% CI, 0.4-8.0 minutes) in the fibrinogen group and 8.7 minutes (95% CI,
5.2-12.1 minutes) in the control group.

However, other than these times do
suggest these were not the best and fastest surgeons ever. This is why the
primary endpoint was different than we expected. We expected that the moment
there is a bleeding patient everyone would wait for closure and this would lead
to a difference in blood loss in the patient and of course a difference in the
intraoperative time factor.

Secondary outcomes

There were fewer patients in the fibrinogen group and fewer
units of blood units used (Table 2). However, the study was not adequately
powered to test the secondary outcomes. The percentage of reduction in transfusion
is shown in Figure 3.

After surgery, a single patient (2%) in the fibrinogen group
and 6 patients (10%) in the control group received additional fibrinogen
concentrate. This confounds the effect on overall outcomes.

Procoagulants and antifibrinolytics use is shown in Table 3.
The percentage of reduction is shown in Figure
4.

Clinical adverse events within 30 days

There were more adverse events in the fibrinogen group
(Table 4). Two patients died, and 4 suffered a stroke. One patient in the
control group suffered a stroke, and one a transient ischaemic attack. The
trial was not designed to evaluate major adverse cardiac events and there was
no screening for embolic risk aortic disease.

Almost 50% (9/19) of adverse events occurred in two patients
(Table 5) (see p. VIII). Also one stroke occurred in a placebo patient with a
fibrinogen level of 0.6g/l.

Transfusion protocol for cardiac surgery

At Isala Clinics we now use the following transfusion
protocol (Figure 5). We conduct viscoelastic tests (ROTEM) to guide
haemostatic therapies. Maegele and colleagues have provided a useful
haemotherapy algorithm (Maegele et al. 2017).

Conclusion

Fibrinogen is effective after complex cardiac surgery in the
bleeding patient. Based on the current trial data, fibrinogen is recommended as
a first-line therapy with target plasma level 2.5g/L at the moment there is an
idea of microvascular bleeding in these patients. Both visco-elostometry as the
conventional Clauss method can be used to determine the level of fibrinogen at
the end of bypass surgery and to optimise further treatment.

We have the tools
and knowledge now to change transfusion management. But changing transfusion
management, as with any change, is a major behavioural process. You need to do
this together with your own multidisciplinary group, using a change strategy
such as the Kotter model (https://www.kotterinternational.com/8-stepsprocess-for-leading-change).

Conflict of Interest

Arno Nierich is the principal investigator for the
fibrinogen concentrate trial at Isala Clinics. CSL Behring sponsored the study and
donated the bottles of study medication.

Key Points

Implement transfusion management with change strategy

Multidisciplinary group essential

Point-of-care and lab monitoring:

Part of overcoming
the ’blind spot’ of coagulation management in operating room and intensive care
unit

Additional tool in fine-tuning bleeding management

Measure fibrinogen level by Clauss as first potential
bleeding indication

Fibrinogen is effective after complex cardiac surgery in the
bleeding patient: from rescue medication to first-line therapy with target
level 2.5 g/L in the bleeding patient

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